CS3: Glucose-6-Phosphate Dehydrogenase (G6PD)

What is G6PD deficiency?

Glucose-6-phosphate dehydrogenase deficiency

• X-linked recessive genetic disorder causing premature lysing of red blood cells (hemolysis) and resulting in hemolytic anaemia

• Affects males more than female (X chromosome carries G6PD deficiency)

What causes G6PD deficiency?

• X-linked recessive disorder results in the decreased activity of the G6PD enzyme

• G6PD protects red blood cells from oxidative stress

• Deficiency leads to decreased synthesis of NADPH and glutathione (antioxidants) from the pentose phosphate pathway

Pentose phosphate pathway → Uses 1 molecule of NADP+ to produce 1 molecule of NADPH

How does G6PD reduce oxidative stress?

1. Glucose is taken up by the cell is converted to Glucose 6-phosphate

2. Glucose 6-phosphate either enters glycolysis or Pentose phosphate pathway

   • If glycolysis: Glucose 6-phosphate is oxidized in glycolytic pathway to produced lactate

   • If Pentose phosphate pathway: Glucose 6-phosphate is converted to 6-Phospho-gluconate by Glucose 6-phosphate dehydrogenase, (while producing NADPH) then it enters hexose monophosphate (HMP) shunt, which is the alternative pathway to glycolysis

3. Glutathione reductase uses NADPH produced & oxidized glutathione to produce 2 molecules of reduced glutathione (2GSH)

4. Reduced glutathione & H2O2 is converted to oxidized glutathione & water by Glutathione peroxidase

   • H2O2 is produced as a result of oxidative stress

   • H2O2 is toxic to cell, if it is allowed to increase to large amts, it will kill the cell

   • If there is no reduced glutathione, then glutathione peroxidase will not function → H2O2 builds up in the cell

In summary:

Deficiency in G6PD → No NADPH formed → Glutathione reductase cannot convert oxidized glutathione to reduced glutathione → Glutathione peroxidase cannot convert reduced glutathione and H2O2 into water → Under oxidative stress, H2O2 builds up to high level → Kills cell, hemolytic anemia

What can trigger G6PD deficiency?

• Use of certain drugs

• Infections

• Consumption of fava beans → increases levels of reactive oxygen species = destruction of RBC faster than replacement